背景:多PDZ结构域面包屑细胞极性复合物成分(MPDZ)与一些人类癌症有关。然而,MPDZ在结直肠癌(CRC)进展中的作用和潜在机制尚不清楚.
方法:在TCGA和GEO队列中,通过Kaplan-Meier方法和单因素回归分析确定MPDZ在CRC中的预后作用.GSEA代表KEGG,进行Hallmark和GO以表征MPDZ涉及的关键途径。通过计算TCGA和GEO数据评估免疫浸润和免疫治疗结果。CCK8,EDU,transwell和伤口愈合试验用于评估MPDZ对CRC细胞有害性能的影响。将CD8+T细胞和CRC细胞共培养以探讨MPDZ对肿瘤微环境的影响。qRT-PCR,westernblot,免疫沉淀(IP)和甲基化RNA免疫沉淀(me-RIP)用于寻找MPDZ在CRC中的潜在机制。
结果:MPDZ表达升高的CRC患者的预后明显较差。同时,MPDZ可能是CRC的独立预后风险指标。GSEA分析显示,MPDZ参与了与CRC转移和细胞周期相关的通路。此外,MPDZ的表达与几种免疫抑制剂有关,并具有预测免疫治疗反应的能力。最后,体外实验表明,MPDZ敲低抑制迁移,CRC细胞的侵袭和免疫逃避。机械上,MPDZ敲低通过增加LATS1表达来增强YAP1磷酸化,从而抑制上皮间质转化(EMT)和CRC细胞的免疫逃避。此外,m6A-MPDZmRNA可被m6A识别蛋白YTHDF2识别和降解。
结论:MPDZ对于CRC的发展至关重要,并且可能是CRC患者免疫治疗联合治疗的有希望的候选者。
Multiple PDZ Domain Crumbs Cell Polarity Complex Component (
MPDZ) is involved in a few human cancers. However, the features and potential mechanisms of MPDZ in progression of colorectal cancer (CRC) remains unknown.
The prognostic role of MPDZ in CRC was determined by Kaplan-Meier and univariate regression analysis. Enrichment analysis was performed to characterize crucial pathways of
MPDZ. Immune infiltration and immunotherapeutic outcome were further evaluated. CCK8, EDU, transwell, and wound healing assay were used to assess the influence of MPDZ on pernicious performance of CRC cells. CD8+ T cells and CRC cells were co-cultured to explore the effect of MPDZ on the tumor microenvironment. qRT-PCR, western blot, immunoprecipitation (IP), and methylated RNA immunoprecipitation (me-RIP) were implemented in seeking for the potential mechanisms of MPDZ in CRC.
CRC patients with elevated
MPDZ expression suffered from significantly worse prognosis. Enrichment analysis revealed that MPDZ involved in pathways related to metastasis and cell cycle in CRC. In addition, MPDZ expression were related to several immunoinhibitors and had the ability to predict immunotherapy response. Finally, in vitro assays demonstrated that MPDZ knockdown inhibited migration, invasion and immune evasion of CRC cells. Mechanistically,
MPDZ knockdown enhanced YAP1 phosphorylation by increased LATS1 expression. Moreover, m6A-
MPDZ mRNA may be recognized and degraded by m6A recognition protein YTHDF2.
MPDZ was critical for CRC development and could be a promising candidate for the treatment of CRC patients.